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Cutaneous sclerotic chronic graft-versus-host disease (cGVHD) is a common and highly morbid complication of allogeneic hematopoietic stem cell transplantation. Our goals were to identify signals active in the skin of patients with sclerotic cGVHD in an effort to better understand how to treat this manifestation and to explore the heterogeneity of the disease. We identified genes that are significantly upregulated in the skin of patients with sclerotic cGVHD (n = 17) compared with those in the skin of patients who underwent allogeneic hematopoietic stem cell transplantation without cutaneous cGVHD (n = 9) by bulk RNA sequencing. Sclerotic cGVHD was most associated with T helper 1, phagocytic, and fibrotic pathways. In addition, different transcriptomic groups of affected patients were discovered: those with fibrotic and inflammatory/T helper 1 gene expression (the fibroinflammatory group) and those with predominantly fibrotic/TGFβ-associated expression (the fibrotic group). Further study will help elucidate whether these gene expression findings can be used to tailor treatment decisions. Multiple proteins encoded by highly induced genes in the skin (SFRP4, SERPINE2, COMP) were also highly induced in the plasma of patients with sclerotic cGVHD (n = 16) compared with those in plasma of control patients who underwent allogeneic hematopoietic stem cell transplantation without sclerotic cGVHD (n = 17), suggesting these TGFβ and Wnt pathway mediators as candidate blood biomarkers of the disease.